Published online April 28, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1438-e1440 (doi:10.1542/peds.2007-2709)

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EXPERIENCE & REASON

Prolonged Neonatal Jaundice and the Diagnosis of Biliary Atresia: A Single-Center Analysis of Trends in Age at Diagnosis and Outcomes

Sharad I. Wadhwani, BA, Yumirle P. Turmelle, MD, Rosemary Nagy, MBA, RD, Jeffrey Lowell, MD, Patrick Dillon, MD and Ross W. Shepherd, MD

Division of Gastroenterology, St Louis Children's Hospital, Departments of Pediatrics and Surgery, Washington University School of Medicine, St Louis, Missouri

ABSTRACT

Age at diagnosis is a modifiable risk factor in outcomes after hepatoportoenterostomy in biliary atresia; however, distinguishing biliary atresia from other more common causes of prolonged neonatal jaundice can be difficult. To focus attention on diagnosis of biliary atresia, we analyzed secular trends in the age at diagnosis, and other factors that might influence outcome. We performed a retrospective analysis of 55 consecutive infants with biliary atresia presenting to a single academic pediatric center over 15-year period from 1990 to 2004. The median age at diagnosis was 60 days (range: 21–152). In recent era (2000–2004), the median age was 69.0 days, compared with 48.5 days (1990–1994) and 59.5 days (1995–1999), respectively. Consistent with previous studies, the median age at diagnosis of those with poor outcomes (death or liver transplant) exceeded those with good outcomes after the hepatoportoenterostomy (72 vs 52 days, P < .001). The lack of improvement, or a concerning trends toward an increase in the age at diagnosis of biliary atresia, is perhaps attributable to neonatal follow-up practices. Efforts to make an earlier diagnose of this important condition deserve wider application and study.

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Key Words: neonatal jaundice • biliary atresia • conjugated bilirubinemia

Abbreviations: BA, biliary atresia • KP, Kasai portoenterostomy • BARC, Biliary Atresia Research Consortium

Biliary atresia (BA) is an uncommon, but important, cause of prolonged neonatal jaundice. This idiopathic obliterative cholangiopathy rapidly leads to liver cirrhosis and liver failure if untreated.¹ A timely hepatoportoenterostomy, or Kasai portoenterostomy (KP), alters this natural history.^2–4 The KP may restore bile flow and help prevent progression of the liver injury, potentially enhancing survival without liver transplantation.^3–6 Thus, age at diagnosis of BA is a potentially modifiable risk factor.^2,4,6 We analyzed secular trends in the age at diagnosis, and other factors that might influence the outcome of BA at a single academic pediatric center over a 15-year period to help focus attention on areas of management where improved outcomes might be realized.

METHODS

This is an Institutional Review Board-approved retrospective analysis of data relating to all infants diagnosed with BA by operative cholangiogram, undergoing a KP, presenting at St Louis Children's Hospital since 1990 with at least 2 years of follow-up (n = 55). Age at diagnosis was evaluated according to era (era I: 1990–1994, n = 14; era II: 1995–1999, n = 20; and era III: 2000–2004, n = 21), outcome, gender, race, and ethnicity. Outcomes, defined as "good"(survived with native liver), or "poor" (required liver transplant or died) at 2 years old, were analyzed according to age at KP, era, KP surgeon experience (<5 vs 5 KPs performed during this study), conjugated bilirubin 2 to 4 months after KP. Age at diagnosis was analyzed by comparing medians because of skewed age ranges. Statistical analysis was performed by using the ² method, the standard 2-tailed t test, or the 2-year Kaplan-Meier survival analysis as appropriate.

RESULTS

The overall median age at diagnosis of BA was 60 days (mean: 65 days), ranging from 21 to 152 days (Fig 1A). Although not significant on ² analysis, the median age at diagnosis trended later across the era from 48.5 days for 1990 to 1994 (n = 14), to 60.0 days for 1995 to 1999, to 69.0 days for 2000 to 2004 (n = 21), with a significant difference observed comparing eras I and III (P < .05, Fig 1A). The median age at diagnosis of those with a good outcome was 52 days, compared with 72 days for those with a poor outcome (64 days for those who were transplanted, and 76 days for those who died [P < .01, Fig 1B]). Age at KP was not significantly affected by gender, race, or ethnicity (data not shown).

View larger version (14K): [in this window] [in a new window]   FIGURE 1 Median age at diagnosis of BA according to era and outcome. A, Overall median age at diagnosis was 60 days of age, 48.5 days from 1990 to 1994, and 69.0 from 2000 to 2004. B, Those with a good outcome at 2 years, defined as survived with the native liver, had a median age at diagnosis of 52 days, whereas those with poor outcome at 2 years, defined as those liver transplanted or who died, had a median age at diagnosis of 72 days (P < .01).

 
Overall, at 2 years, 40% survived with their native liver, 56% of patients had liver transplants at a median age of 41.8 weeks, and 4% of patients had died. There was no significant era effect on time to transplant, although there was a trend for an earlier age of receiving a transplant for 2000 to 2004, where median age at transplant was 37.9 weeks, compared with 45.7 weeks for 1995 to 1999. The Kaplan-Meier survival analyses stratified by age at KP (<30 days, 30–100 days, and >100 days) are shown in Fig 2A. Significant differences in outcomes were seen between the 3 groups (P < .01). Those diagnosed at >100 days had a universally poor outcome. There was no significant difference in liver survival according to surgical experience of performing <5 or >5 KPs (8 different surgeons, 4 performing >5 KPs each in this study). Clearance of jaundice by 3 months after the KP was associated with better survival of the native liver, than those who remained jaundiced (60% vs 15%, P < .001, Fig 2B).

View larger version (10K): [in this window] [in a new window]   FIGURE 2 Kaplan-Meier survival analysis of native liver in patients with BA after KP. A, Depiction of outcomes according to age group, divided into <30 days, 30 to 100 days, and >100 days. Those who had KP at >100 days had significantly and universally worse outcomes than those diagnosed at <30 days and 30 to 100 days (P < .01). B, Comparison of outcomes by conjugated bilirubin at 3 months after KP at >2.0 or <2.0 (P < .001).

 

DISCUSSION

There has been no improvement in the age at diagnosis of BA over the past 15 years. Indeed, there is a concerning trend toward an increase, with many patients still being diagnosed far too late. The overall mean age at diagnosis of 65 days, ranging from 21 to 152 days, is similar to that reported by the Biliary Atresia Research Consortium (BARC) of 9 referral centers in the United States,⁵ where, between 1999 and 2003, the mean age at diagnosis was 61 days, ranging from 11 to 153 days. In this article, factors such as gender and ethnicity did not affect the age of diagnosis. In the BARC study,⁵ age at diagnosis was more delayed in blacks (72 days) and Hispanic Americans (76 days).

It is important to note that, in this study, the median age at diagnosis of those with poor outcomes far exceeded those with good outcomes after the KP (72 vs 52 days), and those diagnosed at >100 days had a universally poor outcome, which is consistent with previous studies that suggest outcomes are better if the KP is performed at <60 to 90 days, and are worse if performed after 90 to 120 days.^4–8 Thus, in the United States, efforts to improve the current average age of diagnosis of 60 days and certainly to make this diagnosis before 100 days deserve serious consideration.

BA is a rare disease (1 in 14 000 births in the United States). The earliest symptoms of BA include prolonged neonatal jaundice, which manifests as conjugated hyperbilirubinemia, acholic stools, dark urine, and hepatomegaly. Diagnosis can only be ultimately made by operation findings and cholangiogram after a series of screening tests. Benign causes of prolonged jaundice, manifested as unconjugated hyperbilirubinemia, are common in breastfed infants. Liver diseases, manifested primarily as conjugated hyperbilirubinemia, account for 1 in 500 instances of jaundice in 2- to 4-week-old children,⁹ the time at which the diagnosis of BA might most appropriately be made. Mixing of stools and urine in a diaper may cloud interpretation of acholic stools. In Taiwan, the use of a stool color card to diagnose BA has effectively decreased the age of diagnosis.¹⁰ Analysis of serum-conjugated bilirubin is technically not available for mass screening. Also, unfortunately, the currently recommended postnatal visit schedule in the United States calls for visits at 2 months of age, rather than 2 to 4 weeks of age, the timing of which is not optimal for diagnosing BA. This latter issue, recommended only in the past 10 years, perhaps explains our finding that the secular trend for age at diagnosis has not improved, or has perhaps worsened.

These observations have some limitations. From this prospective single-center study, it is not possible to ascertain the true optimal age at diagnosis. It is possible that other factors affecting outcomes such as surgical center experience and the variable phenotypic features of BA are confounding factors.¹ In particular, some patients have the more severe "embryonal" form of BA with a worse prognosis,^5,11 explaining the confounding outcomes for those diagnosed at <30 days in this study. Such questions can only be answered by large prospective multicenter studies, currently undertaken by the BARC.¹² In the meantime, greater awareness of this disease and better communication between centers of expertise in BA and community pediatricians could lead to earlier diagnosis. Stool color cards in pediatricians' offices could be used to screen jaundiced infants,¹⁰ leading to conjugated bilirubin analyses. Subsequent studies should focus on various techniques to identify this disease earlier, thus improving outcome from the KP and reducing the need for liver transplantation.

FOOTNOTES

Accepted Nov 2, 2007.

Address correspondence to Yumirle P. Turmelle, MD, Department of Pediatric Gastroenterology and Nutrition, Washington University School of Medicine, One Children's Place, Campus Box 8116, St Louis, MO 63110. E-mail: Turmelle_y{at}kids.wustl.edu

Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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